tbuckley/cabot-search huggingface dataset:
Reprogramming of cancer-associated fibroblasts by apoptotic cancer cells inhibits lung metastasis via Notch1-WISP-1 signaling
Authors: Hee Ja Kim, Kyungwon Yang, Kiyoon Kim, Ye‐Ji Lee, Sieun Lee, Sung Yong Ahn, Young‐Ho Ahn, Jihee Lee Kang
Journal: Cellular and Molecular Immunology (2022)

The interplay between apoptotic cancer cells and the tumor microenvironment modulates cancer progression and metastasis. Cancer-associated fibroblasts (CAFs) play a crucial role in promoting these events through paracrine communication. Here, we demonstrate that conditioned medium (CM) from lung CAFs exposed to apoptotic cancer cells suppresses TGF-β1-induced migration and invasion of cancer cells and CAFs. Direct exposure of CAFs to apoptotic 344SQ cells (ApoSQ) inhibited CAF migration and invasion and the expression of CAF activation markers. Enhanced secretion of Wnt-induced signaling protein 1 (WISP-1) by CAFs exposed to ApoSQ was required for these antimigratory and anti-invasive effects. Pharmacological inhibition of Notch1 activation or siRNA-mediated Notch1 silencing prevented WISP-1 production by CAFs and reversed the antimigratory and anti-invasive effects. Enhanced expression of the Notch ligand delta-like protein 1 on the surface of ultraviolet-irradiated apoptotic lung cancer cells triggered Notch1-WISP-1 signaling. Phosphatidylserine receptor brain-specific angiogenesis inhibitor 1 (BAI1)-Rac1 signaling, which facilitated efferocytosis by CAFs, participated in crosstalk with Notch1 signaling for optimal production of WISP-1. In addition, a single injection of ApoSQ enhanced WISP-1 production, suppressed the expression of CAF activation markers in isolated Thy1+ CAFs, and inhibited lung metastasis in syngeneic immunocompetent mice via Notch1 signaling. Treatment with CM from CAFs exposed to ApoSQ suppressed tumor growth and lung metastasis, whereas treatment with WISP-1-immunodepleted CM from CAFs exposed to ApoSQ reversed the antitumorigenic and antimetastatic effects. Therefore, treatment with CM from CAFs exposed to apoptotic lung cancer cells could be therapeutically applied to suppress CAF activation, thereby preventing cancer progression and metastasis.
Alexander Munn
Authors: Gabriel Gabriel
Journal: BMJ (2022)

An immunohistochemical study of glutathione S-transferase (GST) expression in hepatocellular carcinoma and cholangiocarcinoma is described. Unlike most animal models of hepatic malignancy pi class GST was not consistently overexpressed in hepatocellular carcinoma. This tumour type either predominantly expressed alpha class GST or failed to express GST. By contrast, cholangiocarcinoma always expressed pi class GST, presumably reflecting the tissue of origin, since in human biliary epithelium pi class GST is the predominant GST. The variable expression of pi class GST which was observed in hepatocellular carcinoma may reflect transformation of hepatocytes damaged by toxins, since this GST can be induced after a chemical insult such as alcohol. As well as indicating the biochemical heterogeneity of hepatocellular carcinoma with respect to GST, this study indicates the need for further study of the nature of inherent drug resistance in these tumour types.
David John Austin
Authors: Liz Austin
Journal: BMJ (2022)

Differentiation of naive CD4<sup>+</sup> cells into Th2 cells is accompanied by chromatin remodeling at the Th2 cytokine locus allowing the expression of the IL-4, IL-5, and IL-13 genes. In this report, we investigated the role in Th2 differentiation of the transcription regulator CCCTC-binding factor (CTCF). Chromatin immunoprecipitation analysis revealed multiple CTCF binding sites in the Th2 cytokine locus. Conditional deletion of the <i>Ctcf</i> gene in double-positive thymocytes allowed development of peripheral T cells, but their activation and proliferation upon anti-CD3/anti-CD28 stimulation in vitro was severely impaired. Nevertheless, when TCR signaling was circumvented with phorbol ester and ionomycin, we observed proliferation of CTCF-deficient T cells, enabling the analysis of Th2 differentiation in vitro. We found that in CTCF-deficient Th2 polarization cultures, transcription of IL-4, IL-5, and IL-13 was strongly reduced. By contrast, CTCF deficiency had a moderate effect on IFN-γ production in Th1 cultures and IL-17 production in Th17 cultures was unaffected. Consistent with a Th2 cytokine defect, CTCF-deficient mice had very low levels of IgG1 and IgE in their serum, but IgG2c was close to normal. In CTCF-deficient Th2 cultures, cells were polarized toward the Th2 lineage, as substantiated by induction of the key transcriptional regulators GATA3 and special AT-rich binding protein 1 (SATB1) and down-regulation of T-bet. Also, STAT4 expression was low, indicating that in the absence of CTCF, GATA3 still operated as a negative regulator of STAT4. Taken together, these findings show that CTCF is essential for GATA3- and SATB1-dependent regulation of Th2 cytokine gene expression.
PARP1-MGMT complex underpins pathway crosstalk in O6-methylguanine repair
Authors: Jodie D. Cropper, Dauren S. Alimbetov, Kevin T. G. Brown, Rostislav I. Likhotvorik, Andrew J. Robles, James T. Guerra, Boxue He, Yidong Chen, Youngho Kwon, Raushan T. Kurmasheva
Journal: Journal of Hematology & Oncology (2022)

Abstract DNA lesions induced by alkylating agents are repaired by two canonical mechanisms, base excision repair dependent on poly(ADP) ribose polymerase 1 (PARP1) and the other mediated by O 6 -methylguanine (O 6 meG)-DNA methyltransferase (MGMT) in a single-step catalysis of alkyl-group removal. O 6 meG is the most cytotoxic and mutagenic lesion among the methyl adducts induced by alkylating agents. Although it can accomplish the dealkylation reaction all by itself as a single protein without associating with other repair proteins, evidence is accumulating that MGMT can form complexes with repair proteins and is highly regulated by a variety of post-translational modifications, such as phosphorylation, ubiquitination, and others. Here, we show that PARP1 and MGMT proteins interact directly in a non-catalytic manner, that MGMT is subject to PARylation by PARP1 after DNA damage, and that the O 6 meG repair is enhanced upon MGMT PARylation. We provide the first evidence for the direct DNA-independent PARP1-MGMT interaction. Further, PARP1 and MGMT proteins also interact via PARylation of MGMT leading to formation of a novel DNA damage inducible PARP1-MGMT protein complex. This catalytic interaction activates O 6 meG repair underpinning the functional crosstalk between base excision and MGMT-mediated DNA repair mechanisms. Furthermore, clinically relevant ‘chronic’ temozolomide exposure induced PARylation of MGMT and increased binding of PARP1 and MGMT to chromatin in cells. Thus, we provide the first mechanistic description of physical interaction between PARP1 and MGMT and their functional cooperation through PARylation for activation of O 6 meG repair. Hence, the PARP1-MGMT protein complex could be targeted for the development of advanced and more effective cancer therapeutics, particularly for cancers sensitive to PARP1 and MGMT inhibition.
MED1 Regulates BMP/TGF-β in Endothelium: Implication for Pulmonary Hypertension
Authors: Chen Wang, Yuanming Xing, Jiao Zhang, Ming He, Jianjie Dong, Shanshan Chen, Haoyu Wu, Hsi-Yuan Huang, Chih-Hung Chou, Liang Bai, Fangzhou He, Jianqing She, Ailing Su, Youhua Wang, Patricia A. Thistlethwaite, Hsien-Da Huang, Jason X.-J. Yuan, Zu-Yi Yuan, John Y-J. Shyy
Journal: Circulation Research (2022)

Dysregulated BMP (bone morphogenetic protein) or TGF-β (transforming growth factor beta) signaling pathways are imperative in idiopathic and familial pulmonary arterial hypertension (PAH) as well as experimental pulmonary hypertension (PH) in rodent models. MED1 (mediator complex subunit 1) is a key transcriptional co-activator and KLF4 (Krüppel-like factor 4) is a master transcription factor in endothelium. However, MED1 and KLF4 epigenetic and transcriptional regulations of the BMP/TGF-β axes in pulmonary endothelium and their dysregulations leading to PAH remain elusive. We investigate the MED1/KLF4 co-regulation of the BMP/TGF-β axes in endothelium by studying the epigenetic regulation of BMPR2 (BMP receptor type II), ETS-related gene (ERG), and TGFBR2 (TGF-β receptor 2) and their involvement in the PH.High-throughput screening involving data from RNA-seq, MED1 ChIP-seq, H3K27ac ChIP-seq, ATAC-seq, and high-throughput chromosome conformation capture together with in silico computations were used to explore the epigenetic and transcriptional regulation of BMPR2, ERG, and TGFBR2 by MED1 and KLF4. In vitro experiments with cultured pulmonary arterial endothelial cells (ECs) and bulk assays were used to validate results from these in silico analyses. Lung tissue from patients with idiopathic PAH, animals with experimental PH, and mice with endothelial ablation of MED1 (EC-MED1-/-) were used to study the PH-protective effect of MED1.Levels of MED1 were decreased in lung tissue or pulmonary arterial endothelial cells from idiopathic PAH patients and rodent PH models. Mechanistically, MED1 acted synergistically with KLF4 to transactivate BMPR2, ERG, and TGFBR2 via chromatin remodeling and enhancer-promoter interactions. EC-MED1-/- mice showed PH susceptibility. In contrast, MED1 overexpression mitigated the PH phenotype in rodents.A homeostatic regulation of BMPR2, ERG, and TGFBR2 in ECs by MED1 synergistic with KLF4 is essential for the normal function of the pulmonary endothelium. Dysregulation of MED1 and the resulting impairment of the BMP/TGF-β signaling is implicated in the disease progression of PAH in humans and PH in rodent models.
Boosting Doxorubicin‐Induced Mitochondria Apoptosis for the Monodrug‐Mediated Combination of Chemotherapy and Chemodynamic Therapy
Authors: Tao Liu, Cheng‐Feng Xiong, Lin‐Jun Zhang, Guan‐Hua Jiao, Hui Shi, Jun Feng, Xian‐Zheng Zhang
Journal: Advanced Healthcare Materials (2022)

Doxorubicin (Dox)-mediated generation of reactive oxygen radicals (ROS) for mitochondrial apoptosis is identified as a new cytotoxic mechanism in addition to the well-established one via nuclear DNA replication interference. However, this mechanism contributes far less than the latter to Dox therapy. This newly identified pathway to make Dox therapy function like the combination of chemodynamic therapy (CDT) and chemotherapy-mediated by Dox alone would be amplified. One-pot nanoconstruction (HEBD) is fabricated based on the chemical reactions driven assemblies among epigallocatechin gallate (EGCG), buthionine sulfoximine (BSO) and formaldehyde in aqueous mediums followed by Dox adsorption. Acid tumor microenvironments allow the liberation of EGCG, BSO, and Dox due to the breakage of Schiff base bonds. EGCG component in HEBD is responsible for targeting mitochondria and disrupting mitochondrial electron transport chain (mETC) to compel electrons leakage in favor of their capture by Dox to produce more ROS. EGCG-induced mETC disruption results in mitochondrial respiration inhibition with alleviated hypoxia in tumor cells while BSO inhibits glutathione biosynthesis to protect ROS from redox depletion, further boosting Dox-induced CDT. This strategy of amplifying CDT pathway for the Dox-mediated combined therapy could largely improve antitumor effect, extend lifespan of tumor-bearing mice, reduce risks of cardiotoxicity and metastasis.
Dynamically Crosslinked Poly(ethylene‐glycol) Hydrogels Reveal a Critical Role of Viscoelasticity in Modulating Glioblastoma Fates and Drug Responses in 3D
Authors: Sauradeep Sinha, Manish Ayushman, Xinming Tong, Fan Yang
Journal: Advanced Healthcare Materials (2022)

Glioblastoma multiforme (GBM) is the most prevalent and aggressive brain tumor in adults. Hydrogels have been employed as 3D in vitro culture models to elucidate how matrix cues such as stiffness and degradation drive GBM progression and drug responses. Recently, viscoelasticity has been identified as an important niche cue in regulating stem cell differentiation and morphogenesis in 3D. Brain is a viscoelastic tissue, yet how viscoelasticity modulates GBM fate and drug response remains largely unknown. Using dynamic hydrazone crosslinking chemistry, a poly(ethylene-glycol)-based hydrogel system with brain-mimicking stiffness and tunable stress relaxation is reported to interrogate the role of viscoelasticity on GBM fates in 3D. The hydrogel design allows tuning stress relaxation without changing stiffness, biochemical ligand density, or diffusion. The results reveal that increasing stress relaxation promotes invasive GBM behavior, such as cell spreading, migration, and GBM stem-like cell marker expression. Furthermore, increasing stress relaxation enhances GBM proliferation and drug sensitivity. Stress-relaxation induced changes on GBM fates and drug response are found to be mediated through the cytoskeleton and transient receptor potential vanilloid-type 4. These results highlight the importance of incorporating viscoelasticity into 3D in vitro GBM models and provide novel insights into how viscoelasticity modulates GBM cell fates.
Table of Contents
Authors: Rebekka Jerjen, Mandana Nikpour, Thomas Krieg, Christopher Denton, Amanda Saracino, Dirk Elston, Brett Sloan, Jonathan Kantor, Erin Warshaw, Jenna Ruggiero, Joel Dekoven, Melanie Pratt, Jonathan Silverberg, Howard Maibach, Kathryn Zug, Amber Atwater, James Taylor, Margo Reeder, Denis Sasseville, Joseph Fowler, Anthony Fransway, Donald Belsito, Vincent Deleo, Marie-Claude Houle, Cory Dunnick, Raina Bembry, Beiyu Liu, Michelle Xiong, Nutchaya Amornruk, Noppachai Siranart, Prattana Sittiwattanawong, Patipark Kueanjinda, Suwimon Loplumlert, Jongkonnee Wongpiyabovorn, Nisha Patel, Holly Neale, Isabella Plumptre, Leah Belazarian, Karen Wiss, Elena Hawryluk, Josh Bryer, Esther Freeman, Misha Rosenbach, Michael Woodbury, Jeffrey Cohen, Joseph Merola, Lourdes Perez-Chada, Walter Liszewski, Abu Zaidi, Elise Fournier, Andrew Scheman, Clinton Enos, Julie Yi, Robert Mclean, Adam Sima, Elizabeth Kohl, Thomas Eckmann, Abby Van Voorhees, Stephan Gadola, Petra Fa ¨rber, Maximilian Posch, Sandra Nagel, Filippo Canducci
Journal: Journal of the American Academy of Dermatology (2022)
A nationwide evaluation of bevacizumab-based treatments in pediatric low-grade glioma in the UK: Safety, efficacy, visual morbidity, and outcomes
Authors: Katherine Green, Paraskevi Panagopoulou, Felice D’Arco, Patricia O’Hare, Richard Bowman, Bronwen Walters, Christine Dahl, Mette Jorgensen, Pritesh Patel, Olga Slater, Rehana Ahmed, Simon Bailey, Fernando Carceller, Rhiannon Collins, Elizabeth Corley, Martin English, Lisa Howells, Ahmed Kamal, John-Paul (JP) Kilday, Stephen Lowis, Blanche Lumb, Erika Pace, Susan Picton, Barry Pizer, Ayad Shafiq, Lena Uzunova, Harriet Wayman, Shaun Wilson, Darren Hargrave, Enrico Opocher
Journal: Neuro-Oncology (2022)

Bevacizumab is increasingly used in children with pediatric low-grade glioma (PLGG) despite limited evidence. A nationwide UK service evaluation was conducted to provide larger cohort "real life" safety and efficacy data including functional visual outcomes.Children receiving bevacizumab-based treatments (BBT) for PLGG (2009-2020) from 11 centers were included. Standardized neuro-radiological (RANO-LGG) and visual (logMAR visual acuity) criteria were used to assess clinical-radiological correlation, survival outcomes and multivariate prognostic analysis.Eighty-eight children with PLGG received BBT either as 3rd line with irinotecan (85%) or alongside 1st/2nd line chemotherapies (15%). Toxicity was limited and minimal. Partial response (PR, 40%), stable disease (SD, 49%), and progressive disease (PD, 11%) were seen during BBT. However, 65% progressed at 8 months (median) from BBT cessation, leading to a radiology-based 3 yr-progression-free survival (PFS) of 29%. Diencephalic syndrome (P = .03) was associated with adverse PFS. Pre-existing visual morbidity included unilateral (25%) or bilateral (11%) blindness. Improvement (29%) or stabilization (49%) of visual acuity was achieved, more often in patients' best eyes. Vision deteriorated during BBT in 14 (22%), with 3-year visual-PFS of 53%; more often in patients' worst eyes. A superior visual outcome (P = .023) was seen in neurofibromatosis type 1-associated optic pathway glioma (OPG). Concordance between visual and radiological responses was 36%; optimized to 48% using only best eye responses.BBTs provide effective short-term PLGG control and delay further progression, with a better sustained visual (best > worst eye) than radiological response. Further research could optimize the role of BBT toward a potentially sight-saving strategy in OPG.
Exploiting radiation immunostimulatory effects to improve glioblastoma outcome
Authors: Hala Awada, François Paris, Claire Pecqueur
Journal: Neuro-Oncology (2022)

Abstract Cancer treatment protocols depend on tumor type, localization, grade, and patient. Despite aggressive treatments, median survival of patients with Glioblastoma (GBM), the most common primary brain tumor in adults, does not exceed 18 months, and all patients eventually relapse. Thus, novel therapeutic approaches are urgently needed. Radiotherapy (RT) induces a multitude of alterations within the tumor ecosystem, ultimately modifying the degree of tumor immunogenicity at GBM relapse. The present manuscript reviews the diverse effects of RT radiotherapy on tumors, with a special focus on its immunomodulatory impact to finally discuss how RT could be exploited in GBM treatment through immunotherapy targeting. Indeed, while further experimental and clinical studies are definitively required to successfully translate preclinical results in clinical trials, current studies highlight the therapeutic potential of immunotherapy to uncover novel avenues to fight GBM.
Salmonella Typhimurium outbreak associated with frozen tomato cubes at a restaurant in western Finland, January to February 2021
Authors: Sohvi Kääriäinen, Dorothée Obach, Dafni Katerina Paspaliari, Marjut Tofferi, Arto Nieminen, Annika Pihlajasaari, Henry Kuronen, Anni Vainio, Ruska Rimhanen-Finne
Journal: Eurosurveillance (2022)

Several individuals reported gastrointestinal symptoms following meals consumed in late January 2021 at a restaurant in western Finland. We conducted a retrospective cohort study and defined a case as a person who ate at the lunch restaurant between 27 and 29 January 2021 and had stomach pain, vomiting or diarrhoea and/or a laboratory-confirmed
Non-pharmaceutical interventions in response to the COVID-19 pandemic in 30 European countries: the ECDC–JRC Response Measures Database
Authors: Lorenzo Lionello, Debora Stranges, Tommi Karki, Emma Wiltshire, Chiara Proietti, Alessandro Annunziato, Josep Jansa, Ettore Severi
Journal: Eurosurveillance (2022)

In response to the COVID-19 pandemic, the European Union/European Economic Area (EU/EEA) countries implemented a wide set of non-pharmaceutical interventions (NPIs), sometimes with limited knowledge on their effect and impact on population. The European Centre for Disease Prevention and Control (ECDC) and the European Commission’s Joint Research Centre (JRC) developed a Response Measures Database (ECDC–JRC RMD) to archive NPIs in 30 EU/EEA countries from 1 January 2020 to 30 September 2022. We aimed to introduce a tool for the wider scientific community to assess COVID-19 NPIs effect and impact in the EU/EEA. We give an overview of the ECDC–JRC RMD rationale and structure, including a brief analysis of the main NPIs applied in 2020, before the roll-out of the COVID-19 vaccination campaigns. The ECDC–JRC RMD organises NPIs through a three-level hierarchical structure and uses four additional parameters (‘status’, ‘implementation’, ‘target group’ and ‘geographical representation’) to provide further information on the implementation of each measure. Features including the ready-for-analysis, downloadable format and its agile taxonomy and structure highlight the potential of the ECDC–JRC RMD to facilitate further NPI analysis and optimise decision making on public health response policies.
Trends in the hospital-sector consumption of the WHO AWaRe Reserve group antibiotics in EU/EEA countries and the United Kingdom, 2010 to 2018
Authors: Ria Benkő, Mária Matuz, Zoltán Pető, Klaus Weist, Ole Heuer, Vera Vlahović-Palčevski, Dominique L Monnet, Githa Fungie Galistiani, Hege Salvesen Blix, Gyöngyvér Soós, Edit Hajdú
Journal: Eurosurveillance (2022)

Background In 2019, the World Health Organization published the 21 st Model list of Essential Medicines and updated the Access, Watch Reserve (AWaRe) antibiotics classification to improve metrics and indicators for antibiotic stewardship activities. Reserve antibiotics are regarded as last-resort treatment options. Aim We investigated hospital-sector consumption quantities and trends of Reserve group antibiotics in European Union/European Economic Area countries and the United Kingdom (EU/EEA/UK). Methods Hospital-sector antimicrobial consumption data for 2010–2018 were obtained from the European Centre for Disease Prevention and Control. Antibacterials’ consumption for systemic use (Anatomical Therapeutic Chemical classification (ATC) group J01) were included in the analysis and expressed as defined daily doses (DDD) per 1,000 inhabitants per day. We defined reserve antibiotics as per AWaRe classification and applied linear regression to analyse trends in consumption of reserve antibiotics throughout the study period. Results EU/EEA/UK average hospital-sector reserve-antibiotic consumption increased from 0.017 to 0.050 DDD per 1,000 inhabitants per day over the study period (p = 0.002). This significant increase concerned 15 countries. In 2018, four antibiotics (tigecycline, colistin, linezolid and daptomycin) constituted 91% of the consumption. Both absolute and relative (% of total hospital sector) consumption of reserve antibiotics varied considerably (up to 42-fold) between countries (from 0.004 to 0.155 DDD per 1,000 inhabitants per day and from 0.2% to 9.3%, respectively). Conclusion An increasing trend in reserve antibiotic consumption was found in Europe. The substantial variation between countries may reflect the burden of infection with multidrug-resistant bacteria. Our results could guide national actions or optimisation of reserve antibiotic use.
The lung in inborn errors of immunity: From clinical disease patterns to molecular pathogenesis
Authors: Maria J Gutierrez, Gustavo Nino, Di Sun, Sonia Restrepo-Gualteros, Sarah C Sadreameli, Elizabeth K Fiorino, Eveline Wu, Timothy Vece, James S Hagood, Paul J Maglione, Geoffrey Kurland, Anastassios Koumbourlis, Kathleen E Sullivan
Journal: Journal of Allergy and Clinical Immunology (2022)
USP36 promotes tumorigenesis and drug sensitivity of glioblastoma by deubiquitinating and stabilizing ALKBH5
Authors: Guoqiang Chang, Gloria S Xie, Li Ma, Linlin Li, Hope T Richard
Journal: Neuro-Oncology (2022)

ALKBH5 is aberrantly activated and exerts critical roles in facilitating the development of glioblastoma. However, the underlying activation mechanism by which ALKBH5 protein is increased in glioblastoma is not completely understood. Our study aimed to elucidate the signaling pathways involved in mediating ALKBH5 protein stability.